Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2–4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine–kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.
Highlights
Interstitial lung diseases represent a broad spectrum of lung pathologies that affect the lung parenchyma causing diffuse inflammation and fibrosis [1]
Several studies going inside the pathogenesis of Idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) exhibit great similarity between both diseases concerning the abnormal activation of the signalling pathway, the cellular responses, the activation of lung fibroblasts and their proliferation
Tumour cells and non-malignant stromal cells secrete different growth factors such as TGF-β1, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), tumor necrosis factor (TNF)-α, interleukin 1β (IL-1β), and IL-6 [212,213] that promote cancer-associated fibroblasts (CAFs) trans-differentiation and activation, contributing to a pro-inflammatory profile and carcinogenesis. Considering this all, it is possible to note that there is a similarity between fibrosis and LC, and among the action of the different growth factors, TGF-β represents the key driver signalling for the trans-differentiation of both fibroblasts and CAFs, which are essential in tumour progression and resistance to therapies [214,215]
Summary
Interstitial lung diseases represent a broad spectrum of lung pathologies that affect the lung parenchyma causing diffuse inflammation and fibrosis [1]. Tumor cells together with non-malignant stromal cells trigger CAF activation through inflammatory mediators such as transforming growth factor beta (TGF-β), interleukin (IL)-1, and interleukin (IL)-6 that contribute to inflammation and carcinogenesis [40,41] To this purpose, TGF-β that can be considered as a master molecular regulator of profibrotic signaling, promoting lung cancer progression and triggering mitogenic stimuli to lung cancer cells. Wiley et al [45] demonstrated that the biologically active profibrotic lipids, namely the leukotrienes (LT), are involved in the senescence-associated secretory phenotype (SASP) which represents one of the mechanisms responsible for the progression of pulmonary fibrosis They demonstrated that the LT-rich conditioned medium (CM) of senescent lung fibroblasts triggered profibrotic signalling in modified fibroblasts treated with inhibitors of ALOX5, the main enzyme in LT biosynthesis [45]. This would ameliorate the prognosis, opening the possibility of new therapeutic strategies and improving survival among IPF-LC patients
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